Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is not known whether acute brain injury results in a systemic acute phase response (APR) or whether an APR influences outcome after an insult to the CNS. The present study sought to establish whether brain injury elicits a systemic or local APR. The expression of acute phase protein (APP) mRNA in liver and brain tissues was measured by Taqman reverse transcriptase-polymerase chain reaction after an excitotoxic lesion in the striatum or challenge with a proinflammatory cytokine. N-methyl-d-aspartate (NMDA)-induced brain lesion did not elicit a systemic APR. In contrast, proinflammatory challenge with mouse recombinant interleukin-1beta (mrIL-1beta) resulted in a significant hepatic APP mRNA expression within 6 hours. Thus, an inflammatory challenge that results in a meningitis leads to a hepatic APR, whereas acute brain injury alone, with no evidence of a meningitis, does not produce an APR. This is surprising because NMDA leads to an increase in endogenous IL-1beta synthesis. This suggests that the brain has an endogenous antiinflammatory mechanism, which protects against the spread of inflammation after an acute injury. In the brain, both excitotoxic lesions and proinflammatory challenge resulted in a profound parenchymal upregulation of APP mRNA after 6 and 12 hours in the injected hemisphere. These results suggest that the local APR may play a role as an antiinflammatory mechanism. These findings indicate a potentially pivotal role for peripheral and local APP production on outcome after brain injury.
J Cereb Blood Flow Metab 2002 Mar
PMID:The systemic and local acute phase response following acute brain injury. 1189 37

The present study determined whether gene transfer of human copper/zinc superoxide dismutase-1 (Cu/Zn SOD-1) prevented the autoregulatory impairment of CBF induced by subarachnoid hemorrhage (SAH). After application of recombinant adenovirus (100 microL of 1 x 10(10) pfu/mL, intracisternally) encoding human Cu/Zn SOD-1 3 days before experiments, Cu/Zn SOD-1 activity significantly increased in association with increase in Cu/Zn SOD-1 mRNA and protein expression in the cerebral vasculature of both sham-operated and SAH rats as determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry, and SAH-induced increase in superoxide anion was markedly reduced in accordance with increased nitric oxide production. In line with these findings, rats that received human Cu/Zn SOD-1 therapy showed the prominent restoration of blunted vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim, and the recovery of impaired autoregulatory vasodilation in response to acute hypotension, thereby leading to significant restoration of CBF autoregulation. These results provide a rational basis for application of Cu/Zn SOD-1 gene therapy for protection of the impairment of autoregulatory CBF during the acute stage of SAH.
J Cereb Blood Flow Metab 2003 Jan
PMID:Prevention of impairment of cerebral blood flow autoregulation during acute stage of subarachnoid hemorrhage by gene transfer of Cu/Zn SOD-1 to cerebral vessels. 1250 96

The subunit composition of glutamate receptors affects their functional properties, and could contribute to abnormal electrophysiology in pediatric cortical dysplasia (CD). We examined electrophysiological responses and subunit assembly of N-methyl-D-aspartate (NMDA) receptors in acutely dissociated normal-appearing pyramidal and cytomegalic neurons from CD tissue and normal-appearing pyramidal neurons from non-CD tissue. In most cytomegalic and approximately 30% of normal-appearing pyramidal neurons from CD tissue, NMDA currents showed decreased Mg(2+) sensitivity compared with neurons from non-CD tissue. Ifenprodil had less effect in CD compared with non-CD neurons, indicating a functional loss of NR2B subunits. NMDA-evoked current density was decreased in cytomegalic compared with normal-appearing neurons. Single-cell reverse transcriptase polymerase chain reaction showed that all non-CD neurons expressed NR2B subunit mRNA. By comparison, 22% of pyramidal neurons in CD tissue lacked NR2B mRNA. Immunofluorescence showed a decrease in NR2B subunit expression in cytomegalic neurons and a subset of normal-appearing pyramidal neurons from CD tissue. Taken together, these results demonstrate the presence of NMDA receptors with altered subunit composition and Mg(2+) sensitivity that could contribute to functional abnormalities in CD.
Cereb Cortex 2004 Jun
PMID:NMDA receptor alterations in neurons from pediatric cortical dysplasia tissue. 1505 78

After intracerebral hemorrhage (ICH), many changes of gene transcription occur that may be important because they will contribute to understanding mechanisms of injury and recovery. Therefore, gene expression was assessed using Affymetrix microarrays in the striatum and the overlying cortex at 24 h after intracranial infusions of blood into the striatum of adult rats. Intracerebral hemorrhage regulated 369 of 8,740 transcripts as compared with saline-injected controls, with 104 regulated genes shared by the striatum and cortex. There were 108 upregulated and 126 downregulated genes in striatum, and 170 upregulated and 69 downregulated genes in the cortex. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed upregulation of IL-1-beta, Lipcortin 1 (annexin) and metallothionein 1,2, and downregulation of potassium voltage-gated channel, shaker-related subfamily, beta member 2 (Kcnab2). Of the functional groups of genes modulated by ICH, many metabolism and signal-transduction-related genes decreased in striatum but increased in adjacent cortex. In contrast, most enzyme, cytokine, chemokine, and immune response genes were upregulated in both striatum and in the cortex after ICH, likely in response to foreign proteins from the blood. A number of these genes may contribute to brain edema and cellular apoptosis caused by ICH. In addition, downregulation of growth factor pathways and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway could also contribute to perihematoma cell death/apoptosis. Intracerebral hemorrhage-related downregulation of GABA-related genes and potassium channels might contribute to perihematoma cellular excitability and increased risk of post-ICH seizures. These genomic responses to ICH potentially provide new therapeutic targets for treatment.
J Cereb Blood Flow Metab 2006 Feb
PMID:Brain genomics of intracerebral hemorrhage. 1603 71

In the human brain, the left and right hemispheres are anatomically asymmetric and have distinctive cognitive function, although the molecular basis for this asymmetry has not yet been characterized. We compared gene expression levels in the perisylvian regions of human left-right cortex at fetal weeks 12, 14, and 19 using serial analysis of gene expression (SAGE). We identified dozens of genes with evidence of differential expression by SAGE and confirmed these by quantitative reverse transcriptase-polymerase chain reaction. Most genes with differential levels of expression in the left and right hemispheres function in signal transduction and gene expression regulation during early cortical development. By comparing genes differentially expressed in left and right fetal brains with those previously reported to be differently expressed in human versus chimpanzee adult brains, we identified a subset of genes that shows evidence of asymmetric expression in humans and altered expression levels between chimps and humans. We also compared the coding sequences of genes differentially expressed between left and right hemispheres and found genes that show both asymmetric expression and evidence of positive evolutionary selection in the primate lineage leading to humans. Our results identify candidate genes involved in the evolution of human cerebral cortical asymmetry.
Cereb Cortex 2006 Jul
PMID:Genomic and evolutionary analyses of asymmetrically expressed genes in human fetal left and right cerebral cortex. 1676 3

Neural progenitor cells in the subventricular zone (SVZ) of the lateral ventricular wall give rise to new neurons throughout rodent life. Ischemic stroke induces angiogenesis and neurogenesis. Using laser capture microdissection (LCM) in combination with microarrays containing approximately 400 known genes associated with stem cells and angiogenesis, we investigated gene profiles of SVZ cells in the adult mouse subjected to middle cerebral artery occlusion. Our data revealed that nonstroke SVZ cells expressed sets of genes that are important for neural progenitor cell proliferation, differentiation, and migration. In addition, stroke SVZ cells expressed many genes involved in neurogenesis during embryonic development but were not detected in nonstroke SVZ cells. Stroke upregulated genes were verified by real-time reverse transcriptase-polymerase chain reaction and immunostaining. These data indicate that adult SVZ cells recapture embryonic molecular signals after stroke and provide insight into the molecular mechanisms, which regulate the biological function of neural progenitor cells in the SVZ of adult rodent brain under physiological and stroke conditions.
J Cereb Blood Flow Metab 2007 Mar
PMID:Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. 1683 28

Fast inhibitory synaptic transmission is primarily mediated by synaptically released gamma-aminobutyric acid (GABA) acting on postsynaptic GABA(A) receptors. GABA acting on GABA(A) receptors produces not only phasic but also tonic inhibitions by persistent activation of extrasynaptic receptors. However, the mechanistic characteristics of tonic inhibition in the neocortex are not well-understood. To address this, we studied pharmacologically isolated GABA(A) receptor-mediated currents in neocortical pyramidal neurons in rat brain slices. Bath application of bicuculline blocked miniature inhibitory postsynaptic currents (mIPSCs) and produced an outward shift in baseline holding current (I(hold)). Low concentrations of SR95531, a competitive GABA(A) receptor antagonist, abolished mIPSCs but had no significant effect on I(hold). The benzodiazepine midazolam produced an inward shift in I(hold) by augmenting tonic GABA(A) receptor-mediated currents, which were significantly greater in layer V neurons than in layer II/III. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a relatively higher expressions of alpha1 and alpha5 subunit mRNA in layer V neurons. L-655708, an alpha5 subunit-specific inverse agonist, reduced tonic currents in layer V but not in layer II/III neurons, whereas zolpidem, an alpha1-subunit agonist, exerted equivalent effects in both layers. These data suggest that the alpha1 GABA(A) receptor subunit is generally involved in tonic inhibition in pyramidal neurons of the neocortex, whereas the alpha5 subunit is specifically involved in layer V neurons.
Cereb Cortex 2007 Aug
PMID:Molecular basis for the GABAA receptor-mediated tonic inhibition in rat somatosensory cortex. 1699 4

Neurodegeneration in Alzheimer's disease and various experimental lesion paradigms are associated with an unscheduled upregulation of cell cycle-related proteins, indicating a link between cell cycle reactivation and neuronal death. Recent evidence, however, suggests that at least some of the canonical cell cycle regulators are constitutively expressed in differentiated neurons of the adult brain. Systematic investigations on the constitutive expression of cell cycle regulators in differentiated neurons in vivo, providing the basis for further insights into their potential role under pathological conditions, however, have not been carried out. Here, we demonstrate a constitutive neuronal expression of Cdks 1, 2, and 4; their activators cyclins D, A, B, and E; and their inhibitors p15(Ink4b), p16(Ink4a), p18(Ink4c), p19(Ink4d), p21(Waf1/Cip1), p27(Kip1), and p57(Kip2) within the neocortex of adult mice by western blot and immunocytochemistry. Expression was verified by single-cell reverse transcriptase-polymerase chain reaction applied to individual microscopically identified neurons captured with laser dissection. Immunoprecipitation and in vitro kinase assays revealed that Cdks 1, 2, and 4 are properly complexed to cyclins and exhibit kinase activity. This physiological expression of positive cell cycle regulators in adult neurons is clearly not related to neuronal proliferation. Taken together, our findings demonstrate a constitutive expression of functionally active cyclin-dependent kinases and their regulators in differentiated neurons suggesting a noncanonical role of cell cycle regulators potentially linked to neuronal plasticity and/or stability.
Cereb Cortex 2007 Aug
PMID:Constitutive expression of functionally active cyclin-dependent kinases and their binding partners suggests noncanonical functions of cell cycle regulators in differentiated neurons. 1705 Jun 46

Subunit composition of N-methyl-D-aspartate-type glutamate receptors (NMDARs) dictates their function, yet the ontogenic profiles of human NMDAR subunits from gestation to adulthood have not been determined. We examined NMDAR mRNA and protein development in human dorsolateral prefrontal cortex (DLPFC), an area in which NMDARs are critical for higher cognitive processing and NMDAR hypofunction is hypothesized in schizophrenia. Using quantitative reverse transcriptase-polymerase chain reaction and western blotting, we found NR1 expression begins low prenatally, peaks in adolescence, yet remains high throughout life, suggesting lifelong importance of NMDAR function. In contrast, NR3A levels are low during gestation, surge soon after birth, and decline progressively through adolescence and into adulthood. Because NR3A subunits uniquely attenuate NMDAR-mediated currents, limit calcium influx, and suppress dendritic spine formation, high levels during early childhood may be important for regulating neuroprotection and activity-dependent sculpting of synapses. We also examined whether subunit changes underlie reduced NMDAR activity in schizophrenia. Our results reveal normal NR1 and NR3A protein levels in DLPFC from schizophrenic patients, indicating that NMDAR hypofunction is unlikely to be maintained by gross changes in NR3A-containing NMDARs or overall NMDAR numbers. These data provide insights into NMDAR functions in the developing CNS and will contribute to designing pharmacotherapies for neurological disorders.
Cereb Cortex 2008 Nov
PMID:Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex. 1829 32

In the present study, we observed the expression of toll-like receptor 4 (TLR4) and its downstream signal pathway in peripheral blood monocytes (PBMs) from patients with acute cerebral infarct (ACI). The expression of TLR4 and MyD88 by PBMs was determined by flow cytometry and reverse transcriptase-polymerase chain reaction, and nuclear factor-kappaB (NF-kappaB) activity was detected by electrophoretic mobility shift assay. Ischemia/reperfusion injury-induced cerebral edema, infarction area, and neurologic impairment scores were determined in MyD88 gene knockout mice. The results indicated a significant increase in circulating TLR4(+) monocytes in ACI patients as compared with the control group and the transient ischemia attack (TIA) group. This change paralleled an elevation in TLR4mRNA transcription and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in the ACI and TIA groups. Correlation analysis showed TLR4 expression to significantly correlate with cytokine levels and stroke severity. MyD88mRNA differed insignificantly among the three groups. Compared with wild-type mice, 6 h of cerebral ischemia followed by 24 h of reperfusion did not significantly change cerebral edema, cerebral infarction area, and neurologic impairment scores in MyD88 gene knockout mice. Compared with the control group, serum heat shock protein (HSP) 60 increased significantly in the ACI and TIA groups, leading to NF-kappaB activation in TLR4/CD14-transfected HEK293 cells. It is suggested that upregulated TLR4 expression on PMBs may act as one of the peripheral mechanisms of inflammatory injury after ACI. Moreover, circulating HSP60 may be a ligand for TLR4, which is involved in the peripheral mechanism of inflammatory injury after ACI, possibly through an MyD88-independent signal pathway.
J Cereb Blood Flow Metab 2008 Sep
PMID:Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. 1852 39


<< Previous 1 2 3 Next >>